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Targetable genetic features of primary testicular and primary central nervous system lymphomas
Bjoern Chapuy1, Margaretha G M Roemer2, Chip Stewart3
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
Abstract:
Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.
Insights
Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) share unique genetic alterations, including CDKN2A loss and PD-L1/PD-L2 copy number alterations, offering potential targets for novel therapies.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are aggressive extranodal large B-cell lymphomas (LBCLs).
- These lymphomas often show poor responses to standard treatment regimens, necessitating the identification of novel therapeutic targets.
Purpose of the Study:
- To comprehensively characterize the genetic landscape of PCNSL and PTL.
- To compare the genetic profiles of PCNSL and PTL with other LBCL subtypes like diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL).
- To identify subtype-specific genetic alterations that can serve as targets for precision medicine.
Main Methods:
- Whole-exome sequencing and copy number alteration (CNA) analysis.
- Chromosomal rearrangement analysis.
- Comparative genomic analysis across different LBCL subtypes.
Main Results:
- PCNSLs and PTLs exhibit significant genomic instability, characterized by frequent CDKN2A loss and rare TP53 mutations.
- Oncogenic Toll-like receptor signaling, driven by MYD88 mutations and/or NFKBIZ amplification, is common.
- Frequent 9p24.1/PD-L1/PD-L2 CNAs and translocations were observed, indicating shared mechanisms of immune evasion with PMBL.
Conclusions:
- PCNSLs and PTLs possess distinct genetic signatures that differentiate them from other LBCLs.
- The identified genetic alterations, particularly those affecting immune evasion pathways, provide a rationale for targeted therapeutic strategies.
- Understanding these unique genetic features is crucial for developing more effective treatments for PCNSL and PTL.
